An Expert Review of Spatial Repellents for Mosquito Control August 2020 arctec ref. no.: 1003/CC0942 Principal Investigator: Prof. James Logan BSc, PhD, FRES, Director Responsible Investigator: Dr. Vanessa Chen-Hussey BSc, MSc, PhD Research Assistance: Lisa O’Halloran BSc, MSc, Courtenay Greaves BSc, MSc, Christine Due BSc, MSc, PhD Document Updating and Editing for Publication –Dr. Michael Macdonald, Sc.D. 1 Contents Executive Summary 3 Objectives 6 Methods 7 Interviews 7 Literature Search 7 Past Spatial Repellent Research 8 Ongoing Spatial Repellent Research and Development 19 Laboratory Test Methods and End Points 21 Outline Protocol for Semi-Field Trials of Spatial Repellents 24 Economic Considerations for Spatial Repellents as a Public Health Tool 28 Commercialisation of Spatial Repellents 30 Target Product Profile 32 Regulatory Issues and Policy Status 37 Knowledge Gap Assessment 39 Feasibility of Adoption of Spatial Repellents within Vector Control Campaigns 42 Recommendations on the Development of Spatial Repellents as Vector Control Tools 45 Conclusion 50 Appendix 1. Question Guide for Interviews 58 Appendix 2. Use Case Analysis 59 References 67 2 Executive Summary Spatial repellents (SR) are a potential tool against vector borne disease, but at present most products are targeted to the consumer market. This report examines the potential role of SRs in public health through published and grey literature, and the opinions of academic and industry experts on spatial repellents. While the primary focus is Anopheles, there are promising data showing spatial repellent impact on Aedes- borne diseases and Leishmania vectors. Literature Review and Ongoing Research There is no current consensus on a clear definition of spatial repellents. Generally, they are defined as chemicals that, when air-borne, prevent biting by blood-seeking insects such as mosquitoes. The chemical should therefore create a space where human hosts are safe from bites and potential disease transmission. Chemicals that have been shown to have spatial repellent effects include volatile pyrethroids such as metofluthrin and transfluthrin; botanical compounds such as terpenoids; or volatiles found from human skin and skin bacteria such as 1-methylpiperazine. Historically, DDT was known to have an “excito-repellent” effect in addition to lethality when applied for indoor residual spraying. Spatial repellent actives have been incorporated into a wide range of devices including coils, heat activated vaporisers to passive emanators based on plastic, paper and hessian materials. Laboratory and semi-field trials have shown good levels of efficacy against important vector species such as Anopheles gambiae and Aedes aegypti. Although spatial repellents aim to disrupt host seeking and feeding behaviour, many laboratory tests have concentrated on a killing effect, perhaps because of the predominance of volatile pyrethroids in the early development of spatial repellents. The World Health Organization (WHO) has produced guidelines for testing spatial repellents which recommend that movement away from a host stimulus should be the main outcome, but very few studies were found to use those methods. Semi-field testing may be more appropriate for testing spatial repellents, as the build-up of the volatile within a three-dimensional space can be better simulated. An outline protocol for testing of spatial repellents in a semi-field system is presented, based on WHO recommendations and subsequent published work. For spatial repellents to become an accepted part of the malaria vector control arsenal, most experts agreed that data from randomised controlled trials showing an impact on disease transmission would be necessary. At present, there are data from semi-field trials showing repellency, and where pyrethroids are concerned, mortality data from laboratory trials. So far, one trial in Indonesia has shown an epidemiological effect; a 52% reduction in malaria from the use of spatial repellents. There are two further randomised controlled trials currently underway, one on malaria in Indonesia and another on Aedes-borne diseases in Peru that will help build on this evidence. Other studies that are currently underway include modelling work, which suggests spatial repellents could have a potentially large public impact and may be particularly useful in helping design the next generation of spatial repellents. 3 Economic Considerations and Commercialisation A wide range of products are commercially available for use as spatial repellents/insecticides, primarily for the consumer market, rather than as a public health intervention with varied degrees of efficacy. There not established route to market for spatial repellent products for use as a vector borne disease intervention. The commercialisation model for spatial repellents would be very different to LLINS or IRS, because there is a vibrant repellent consumer market worldwide. A high volume “developed” market should, in theory, bring production costs down, and, therefore, support provision of cheaper spatial repellent products in developing markets. But this needs further examination and consideration. Regulatory and Policy Issues Spatial repellents are usually included with insecticides (where lethality is a primary objective) in most regulatory guidelines, which presents a problem where the product is not designed to kill mosquitos but prevent biting. However, there are regulatory hurdles for getting any product to market, and these did not overly concern most manufacturers. What was desired was a greater acceptance of data produced according to WHO guidelines at the national level, as these better characterise a repellent, rather than insecticidal effect. There was a desire to update the WHO guidelines, to include more up to date methods and input from industry on the outcomes that would be most useful if the data were to be presented to both the WHO PQ system and national regulatory bodies. Target Product Profiles To develop a target product profile for spatial repellents for public health use, a pragmatic approach was used, where an “achievable” product, with currently available spatial repellents, was considered alongside the ideal product. The interviewees gave a variety of opinions on what would be the ideal spatial repellent product. We have provided further consideration, beyond the interviewee comments. Themes pulled out from interviews included a product which was low-cost, with at least 90% protection from biting, light-weight and portable, a requirement to provide protection outdoors as well as indoors (not necessarily one product that can do both), with an effective duration of 3 to 6 months. Note, as described in more detail below, since this review began there has been an evolution in WHO strategy to now focus on a higher-level Preferred Product Characteristic for the overall product class whereas Target Product Profile is more focused on the specific product development. 4 Knowledge Gap Assessment Several knowledge gaps were identified in our understanding of spatial repellents and their impact when used in vector control. Amongst the most important, was the lack of epidemiological evidence of impact. There are some data, and more data are being gathered, but a solid evidence-base is of paramount importance before spatial repellents can be advocated for use in vector control programmes. An area of debate surrounds the definition of a spatial repellent and different types of effects on the vector, which then impacts directly on what would be the most appropriate methods of evaluation. The effect of volatile pyrethroids on the problem of insecticide resistance needs to be addressed before these products can be widely advocated. In addition, their effect on non-target insects was also of concern, particularly when intended for outdoor use. Another knowledge gap exists around the practicalities of designing a spatial product, meaning replacement rate, area of effect and best placement. All of these would potentially change from setting to setting, and spatial repellents would need to remain a flexible intervention to achieve the greatest impact. Current safety data relies heavily on testing of coils, which means that the effects of smoke inhalation are included with the exposure to the active. Toxicity of emanator devices needs to be established, to help improve the acceptance of spatial repellents by some parts of the vector control community. Feasibility and Recommendations There was clear consensus that spatial repellents have a place in vector control, and several potential routes in which spatial repellents could be utilised are highlighted. Firstly, without any further product development, current devices may be used in fast but short-term responses to vector-borne health crises, including humanitarian relief situations or outbreak response. Spatial repellent devices with improved duration may well be suitable to protect people inside or around houses, perhaps as a replacement or even improvement on indoor residual spraying. Spatial repellents can require little in the way of behaviour change from users, so potentially may be more acceptable and easier to implement, particularly in areas aiming for malaria elimination where other interventions such as bed nets or chemoprophylaxis may become unpopular. After the review was completed an appendix on “Use Case Analysis” developed by IVCC has been added. Other challenges that would need to be overcome to make spatial repellents effective vector control tools